Targeting Ligand Core One major challenge in cancer nanotechnology is how to selectively deliver funcfional nanoparticles to cancer cells. The overall thrust of the Targefing Ligand Core is to provide novel targeting ligands that can be used to direct nanoparticles to particular cancer cell types for projects 1, 2 and 3. Two powerful combinatorial library technologies will be used to generate the desired targefing ligands, including single domain antibodies (SDAs), single domain antibody mimics (SDAMs), and 2'-F/2'-OMe RNA aptamers. The use of two different technologies for protein-based and nudeic acid-based biomolecules, respectively, will ensure that the desired targefing ligands will be rapidly identified and made available to the Projects. Specifically, we will create monomeric (milestone 1) and multimeric (milestone 2) SDAs and SDAMS with high affinity and specificity for EGFR, mesothelin, and other promising cancer biomarkers. We will also use a combinafion of cell-SELEX and conventional SELEX to generate 2'-F and 2'-OMe RNA aptamers that can specifically bind to EGFR or mesothelin expressing lung cancer cells (milestone 3). The resulting targeting ligands will incorporate functional groups such as Cys or Lys at site(s) away from the target-binding region, to facilitate site-specific conjugafion with various nanoparticles that are used in Projects 1, 2, and 3.